Rett Syndrome (RS) is a neurodevelopmental disorder affecting almost exclusively female children with an incidence rate of approximately one in 1O,OO-15,OOO live births. Its most characteristic clinical manifestations are severe developmental and cognitive deterioration, sterotypic movements, irregular respiration, autistic behavior and seizures. Neurochemical evaluations have demonstrated a decrease in cholinergic function in cortical and subcortical regions that may underlie some of these symptoms. The goal of this proposal is to investigate the neural mechanisms responsible for this impaired cholinergic function. The elucidation of these mechanisms will provide information that is central to our understanding of the neurobiology of RS. The results will lay the foundation for the development of an entirely new approach to the study of RS and will determine whether the underlying problem in RS is one of neuronal apoptosis or impaired trophic factor function. The proposed biochemical studies will provide important information on regional levels of trophic factors in the brains of RS cases and female controls. The chronic lack of this trophic-factor, and possibly others, would have an enormous impact upon the normal function (and possibly development) of forebrain cholinergic neurons in the RS brain. The proposed histological studies will investigate for evidence of programmed cell death. In addition, these studies will provide quantitative information on the functional integrity of the acetylcholinergic neurons located within the brain of RS girls. The successful completion of these studies will provide fundamental insights into the neurological bases for the decline in cognitive function seen in RS. In addition, a better understanding of the neurochemical and pathological changes that underlie changes in this neural system, and how these changes underlie the specific clinical symptoms associated with RS, may lead to improved diagnostic and/or therapeutic approaches.